Glaucoma is a disease with high prevalence that causes progressive damage and death of retinal ganglion cells (RGCs) resulting in blindness. Our long[unreadable]term goal is to prevent RGC death in the early stages of glaucoma and spare visual function. The objectives of this study are i) to characterize the history of disease in the OBA/2J (02) mouse model of glaucoma as well as in congenic strains with genetically altered pathways of cell death and ii) to determine the modifiability of RGC function upon acute lOP changes. Our central hypothesis is that RGCs undergo a stage of IOP[unreadable]dependent, reversible dysfunction before dying, and that RGC dysfunction is due to impaired tolerance to intraocular pressure (lOP). Our study will include 02 mice with spontaneous lOP elevation and progressive RGC degeneration;a unique congenic strain without lOP elevation and glaucoma;three unique congenic strains with lOP elevation but genetically altered to increase resistance of either RGC dendrites, RGC bodies or RGC axons to stress. Our specific aims are, 1) Characterize the natural structural[unreadable]functional progression of disease in 02 strains, 2) Characterize the modifiability of RGC function to acute lOP insult in 02 strains. We will use state[unreadable]of[unreadable]the[unreadable]art Pattern Electroretinogram (PERG), Cortical Visually Evoked Potentials (VEP) and Optical Coherence Tomography (OCT) as surrogate measures of RGC function and RGC axon number, respectively. PERG losses result from both reduced activity of viable RGCs and lack of activity of dead RGCs. OCT losses result from lack ofaxons of dead RGCs. We will also use a novel, non invasive method for acute lOP elevation/lowering based on changes of body posture. The techniques used in this proposal can also be translated into clinical practice, and the hypotheses tested may also be pivotal in clinical glaucoma. The central hypothesis is supported by strong preliminary results showing that RGC dysfunction precedes RGC death, and that RGC dysfunction may be temporarily exacerbated/improved by physiological lOP elevation/lowering obtained with changes in body posture. The rationale is that this innovative approach will provide a set of physiological markers to detect susceptibility of RGCs and predict their fate. This outcome will have high significance for identifying individuals at high-risk of developing glaucoma damage and determining the necessity of treatment. Our research team includes experts in experimental glaucoma, visual electrophysiology, retinal imaging, biophysics, and biostatistics.